Corticosteroids are in frequent clinical use, are usually dosed empirically, cause a high incidence of adverse reactions, and exhibit many complexities in relating their plasma pharmacokinetics to pharmacologic effects. This project will address gaps pertaining to basic mechanisms and clinical factors determining the distribution, clearance, and pharmacodynamics of the common glucocorticoids: cortisol, prednisolone, methylprednisolone, and dexamethasone. Studies in animal systems (rabbit and rat) will assess the determinants of variable tissue distribution of steroids, particularly whether free or bound drug accesses various tissues, albumin and transcortin binding in plasma, interstitial fluid distribution, blood flow, tissue metabolism, reversible metabolite formation, and receptor and tissue binding. Receptor binding, including in leukocytes, will be evaluated as a factor in both tissue uptake and index of pharmacologic responses. Several measures of steroid effects (adrenal suppression, hepatic enzyme activity, cytosol receptor content, and anti-inflammatory effects) will be quantitated in relation to factors such as: type of steroid, dose, time, drug-interactions (phenytoin, troleandomycin, naproxen), and disease (aging, uremia, obesity). Parallel clinical studies will include the examination of anticonvulsant/dexamethasone interaction, dexamethasone disposition in obesity, and leukocyte receptor binding as a clinical indicator of steroid responsiveness. Pharmacokinetic methods and concepts will be advanced related to plasma and tissue binding, drug-receptor binding, reversible metabolism, transit-time analysis, tissue distribution kinetics, and circadian effects. Comprehensive physiologic pharmacokinetic/ pharmacodynamic animal and mathematical models will be evolved in order to quantitate the mechanisms and kinetics of corticosteroid action. Improved methods for patient drug therapy should result from insight into normal and disturbed patterns of corticosteroid pharmacodynamics.
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